Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ED05P)

• DOT Name: Histone H2B type 1-O (H2BC17)
• Synonyms: H2B-clustered histone 17; Histone H2B.2; Histone H2B.n; H2B/n
• Gene Name: H2BC17
• Related Disease: Systemic lupus erythematosus
• UniProt ID: H2B1O_HUMAN
• PDB ID: 7WLP
• Pfam ID: PF00125
• Sequence:
  MPDPAKSAPAPKKGSKKAVTKAQKKDGKKRKRSRKESYSIYVYKVLKQVHPDTGISSKAM
  GIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRLLLPGELAKHAVSEGTKAVT
  KYTSSK
• Function: Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Viral carcinogenesis (hsa05203)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)
  Cleavage of the damaged purine (R-HSA-110331)
  Meiotic synapsis (R-HSA-1221632)
  Packaging Of Telomere Ends (R-HSA-171306)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Formation of the beta-catenin (R-HSA-201722)
  PRC2 methylates histones and DNA (R-HSA-212300)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  HDACs deacetylate histones (R-HSA-3214815)
  HATs acetylate histones (R-HSA-3214847)
  SIRT1 negatively regulates rRNA expression (R-HSA-427359)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  DNA methylation (R-HSA-5334118)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 (R-HSA-5625886)
  Ub-specific processing proteases (R-HSA-5689880)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  G2/M DNA damage checkpoint (R-HSA-69473)
  RNA Polymerase I Promoter Opening (R-HSA-73728)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Meiotic recombination (R-HSA-912446)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Defective pyroptosis (R-HSA-9710421)
  Amyloid fiber formation (R-HSA-977225)
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  Replacement of protamines by nucleosomes in the male pronucleus (R-HSA-9821993)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histone H2B type 1-O (H2BC17).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Histone H2B type 1-O (H2BC17).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Histone H2B type 1-O (H2BC17).	[13]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone H2B type 1-O (H2BC17).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone H2B type 1-O (H2BC17).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone H2B type 1-O (H2BC17).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Histone H2B type 1-O (H2BC17).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Histone H2B type 1-O (H2BC17).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Histone H2B type 1-O (H2BC17).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histone H2B type 1-O (H2BC17).	[8]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Histone H2B type 1-O (H2BC17).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Histone H2B type 1-O (H2BC17).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone H2B type 1-O (H2BC17).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone H2B type 1-O (H2BC17).	[12]

References

• [1] The molecular mechanism study of insulin in promoting wound healing under high-glucose conditions.J Cell Biochem. 2019 Sep;120(9):16244-16253. doi: 10.1002/jcb.28905. Epub 2019 May 12.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.